Host-parasite relationship
Pathogenictiy and virulence
Pathomechanism, molecular pathogenesis,
virulence factors
Infection and diseases, vaccines
Dr. Joseph Ongrádi
Institute of Medical Microbiology
Semmelweis University
2014
1
Definition of the host and the parasite
• Host: macroorganism, usually multicellular
phylogenetically higher level,
eukaryote (animal, plant)
(it could be prokaryote)
• Parasite: Living on/in the host → damages → can cause disease
obtaining necessities of life from the host
–
–
–
–
non living: unique protein (prion), nucleic acid (viroid)
non living/living: virus
prokaryote: bacterium
microorganism,
eukaryote: microscopic fungi,
microbes
protozoa
helmiths
– vast majority of microorganisms live in the environment, minor
fraction is parasite
– biologically there is no sharp distinction between normal and
pathogenic
2
Host-parasite relationship
• Host: able to exist independently or
might depend on microbes
• Microorganisms:
– saprophytes live in the environment
– symbiosis: macro- and microorganism live
together (association)
• mutualism: advantageous for both (reciprocal benefit)
• commensalism: do not damage each other (neutral)
• parasitism: advantageous for microorganism (unilateral
benefit)
damages to macroorganisms → disease
3
Commensalism and mutualism
in human as host
• Normal microbe flora (bacteria, microscopic fungi)
– on skin and mucous membranes, in gut and vagina →
colonisation
– host cell : microbe cell number = 1:10
– no entry, no penetration, no colonisation inside cells, tissues,
organs
– (in the blood: occasionally, transiently)
• Viruses: no exogenous normal virus flora
– (but: latent viruses /episomal, integrated/ can be shed
symptomless)
– Human endogenous retroviruses (HERV)
• 8% of the genome = self
• they code for vital functions (e.g. placenta)
• Protozoa, helminths: never found in the normal flora
4
Advantages of commensalism/mutualism
• For microorganisms
– shelter and food
– colonisation, but no entry (penetration) into tissues
– (through wounds, very rarely → disease)
• For the host (human)
– to prevent colonisation of harmful microbes (parasites)
• Occupying surface and cell receptors
• Producing antimicrobial compounds
(e.g. lactic acid in vagina, antibiotics)
– processing/degrading food components
• Producing useful metabolites (vitamin K or B12)
5
Parasite microorganisms
• Inducing pathogenic conditions → diseases (>1400 species!)
• Damages for human:
–
–
–
–
entry/penetration from surfaces into tissues → invasivity
passively through wounds (damaged tissue integrity)
actively (enzymes)
multiplication/replication in tissues → pathogenic effects → disease
• Types of parasitism (pathogenicity, being pathogenic)
– obligate parasites: in defined host (range of hosts)
always pathogenic, never found in the normal flora
– facultative parasites: depending on the condition of both host and
microbe, presence of predisposing /risk factors, members of the
normal flora
– opportunistic parasites: member of the environment, not pathogenic
for healthy people, take advantage in case of host disorders (usually
immunosuppression)
6
Predisposing/risk factors enhancing infection I
• For facultative pathogens
– physical ← mental stress
– acute diseases, wounds, burns
– chronic debilitating conditions
Diabetes, alcoholism, drug abuse, nutritional defects, tumours,
leukaemia (combined with immune suppression, see later)
– calculi (urinary tract, bile stone)
– urinary tract obstruction
– certain work conditions
• Medical interventions (diagnostic and/or therapeutical) – iatrogenic
– changes in the normal microbe flora ← antibiotics, other drugs
– surgery, oral surgery (entry of normal, facultative or opportunistic
pathogens)
– prosthetics, catheters (biofilm!)
• Nosocomial infections
– in any health care facility, any source of infection, anybody (patients,
staff, visitors)
7
Predisposing/risk factors enhancing infection II
• For opportunistic microbes
– immune deficiencies/defects
– physiologically weak (newborns, pregnancy, elderly)
immunosenescence determining life expectancy: ≈105 years
• Congenital/connatal immune deficiencies
– T lymphocytes = cellular immunity ↔ intracellular pathogens, protozoa,
helminths
– B lymphocytes = humoral immunity ↔ bacteria, fungi, protozoa
– complex (T+B cells)
– innate immunity (phagocyte functions, interleukin production)
– complement system
• Acquired immune deficiencies
–
–
–
–
medication (corticosteroids, cytostatic drugs)
radiation (environment, medical)
tumours, leukaemia (virus)
infections – especially those replicating in immune cells
viruses: HHV-6, HHV-7, HIV in CD4+ T cells and macrophages
EBV in B cells
several bacteria, protozoa in macrophages
8
Specificity of pathogenicity, pathogenic ability
• Pathogenicity
– ability of the whole population of a given microbe species to elicit
disease in a given host or range of hosts
– species specific, defined genetically in both host(s) and microbe
(yes or no, qualitative)
– Koch postulates → molecular Koch postulates (determination at
molecular level)
• Virulence
– in the level of pathogenicity
– ability to elicit disease by a smaller population (tribe, strain, type) of
the species
– genetically determined in the smaller population only (quantitative)
• High virulence ↔ low virulence ↔ avirulent (virulence is lost)
– increasing virulence: mutations, GMO, bioterrorism
– decreasing virulence: mutations, attenuation
9
Quantitation of virulence
• Virulence can be measured (number of germs)
• How many microbe (or group of microbes) defined among standard
circumstances induces pathological conditions (disease, death) =
dosis, dose
– ID50 = infective dose inducing disease in 50% of hosts
(e.g. in susceptible experimental animal)
– DL50 = dosis lethalis causing death in 50% of hosts
– DL90, DL100, ID100 etc.
– TCID50 = tissue culture infecting dose damaging 50% of cultures
• Small number of germs (1-102) → disease = high virulence
– 1 calicivirus particle → enteritis (resistant to environmental
conditions)
• Large number of germs (≥ 105) → disease = low virulence
– ≥ 105 cholera bacterium → enteritis (extremely sensitive to acidic pH)
10
Factors determining virulence
• Constituents or products of microbes
– genetically determined (but phenotypically dependent)
• Examples of bacterial virulence factors
Non-toxic
Cell surface constituents
• capsule (see later)
• flagella, cilia → motility
• fimbriae → specific ligands (adhesins)
• sex fimbriae (conjugation)
• pili → adherence to host cells
• invasins → specific ligand to enter cells
• glycocalyx/extracellular mucoid
substances → biofilm
Extracellular enzymes
• damaging host cells
Toxic
• exotoxins
• endotoxin
(lipopolysaccharide, LPS)
11
Non-toxic virulence factors of bacteria
• Capsule
– polysaccharide
– polypeptide (Bacillus anthracis, D-glutamic acid)
• Role of the capsule
– protection
• mechanical, physico-chemical
• biological - anti-phagocytic
- masking, hiding other antigens
– antigen variations in one species - immune evasion
– adhesion to host cells
12
Non-toxic virulence factors of bacteria:
extracellular enzymes
• Secreted from living bacteria → exert effect on
host cells
• Examples
– Antiphagocytic effect
•
•
•
•
leukocidines
coagulase
haemolysins
proteases
– Facilitating invasion
•
•
•
•
solubilising cells, tissues of the host
streptokinase (fibrinolysin) – (surgery: cleaning wounds)
collagenase
hyaluronidase
13
Toxic virulence factors: exotoxins
Secreted by living bacteria → effect on host cells
Major characteristics
– polypeptides (mostly A+B subunits), good antigens
– well defined structure and effect
– some of them are coded by bacteriophages
Effect on the host
• effect on host surfaces (extracellularly acting)
– membrane damage (pore formation → loss of nutrients → cell death
– superantigens: APC MHCII + TCR binding → cytokine production → toxic shock
(Staphylococcus aureus: toxic shock syndrome toxin, TSST)
• intracellularly acting
–
–
–
–
A+B toxin (A: toxic effect or the opposite, B: cell surface binding)
inhibition of protein synthesis (diphtheria)
overproduction of mediators, neurotransmitters (acetylcholine → tetanus)
hypersecretion (cholera toxin: Na+, Cl-, etc. → diarrhoea
Measurement of toxicity
– DLM = dosis lethalis minima kills all experimental animals (ng – μg)
14
Superantigens
15
Endotoxin (lipopolysaccharide, LPS)
Gram negative bacteria – cell wall
Major characteristics
• heat stable, conserved in many Gram- bacteria, weakly immunogenic
(as antigen)
Importance
• recognition by innate immunity:
• pathogen associated molecular pattern (PAMP)
• LPS → LPS binding protein → macrophages, B cells, PMNL, platelets
CD14 and TLR4 binding → cell activation → overproduction of
inflammatory mediators (IL-1, -8, TNF-α)
Biological effects:
• beneficial: small amount is immunostimulant (essential for innate immunity)
eliciting inflammation → isolation of infective agents
• malignant: large amount exerts systemic effects
fever, vascular permeability → hypotension, acute phase
proteins, hypoglycaemia, cytokine storm, DIC, thrombosis →
shock →death
16
Structure of LPS
17
Effects of endotoxin
18
Onset of infection
Infection: entry and replication of microorganism in macroorganism
Source of infection
• Exogenic  infected, symptomless
human, animal
ill
carrier
 environmental vehicles (soil, water, food, etc.)
 reservoir: animals (rodents and insects) or humans or
vehicles carrying pathogenic microbes permanently
• Endogenic  from the normal flora (skin, mouth, gut, vagina)
 activation of latent/persistent microbes
Contagious infections: from human to human
Non-contagious infections: not from human to human
1st infection = primary infection → repeated (secondary) infection
19
Transmission of infection
Horizontal spread
• Direct contact
– human-human, animal-human
• Indirect contact
– contaminated environment, objects
skin, mucous membranes
(sexual organs)
• Vehicles
– air-blow – coughing, sneezing, talking → droplet
aerogenic infections
– contaminated water, food
alimentary/oral infections
– blood sucking insects (lice, fleas, ticks, mosquitos)
vector (arthropod → host /direct percutan transmission/ → arthropod)
• Iatrogenic infections
– direct percutaneous infections by contaminated blood/cell/organ donation,
equipments
Vertical spread
• Next generations: transplacental, diaplacental → connatal infection
(immediate or late manifestation)
20
Types of transmission
21
Infection process: entry
Portals of entry (attachment and penetration)
• skin and mucous membranes
injuries (damage of integrity)
direct penetration (arthropods)
• respiratory tract (epithelial or immune cells)
• gastrointestinal tract (epithelial or immune cells)
• urogenital tract (ascending)
Iatrogenic infections
• skin, mucous membranes – wounds
• implanted cells, tissues, organs
• devices – syringes, canules, prosthetics, catheters (urinary tract!)
Nosocomial infection
• in any healthcare setting, any source, any transmission, any portal
of entry, any host (patients, staff, visitor)
22
Microbial infection and shedding
23
Infection process: colonisation, dissemination
Colonisation
• irreversible, at or near to the site of entry
• multiplication of microbes
• local infections (tetanus bacterium, wart viruses)
Dissemination
• spreading in the body – invasion → generalised infection
• tissue damage, in the blood (haematogenic), in the lymphatics
(lymphogenic), canalicular (respiratory tract), ascending (urogenital tract)
Consequence
• microbes are found far from the portal of entry
• large quantity → several pathogenic effects → disease
Incubation time
• symptomless period between the moment of infection (frequently
unknown) to the onset of symptoms/disease outbreak
• few hours – more months (HBV)
• several years – decades (protozoa, tumour viruses, prions)
24
Infection process: generalization
Dissemination, invasion
Extremely harmful if found in the bloodstream:
• bacterium – bacteriaemia
• virus – viraemia
• parasite (protozoon, helmith) – parasitaemia
• fungus – fungaemia
• toxin – toxaemia
Sepsis
• Infection → systemic inflammatory response syndrome (SIRS)
generalized weakness, malaise, warm skin, rash
high (>38°C) or low (<36°C) body temperature
tachycardia (>90/min)
tachypnoe (>20/min)
WBC (10-12x109/L)
• Aggravation: organ hypoperfusion
• Septic shock: hypotension (systolic BP <90mmHg) resistant to medications
• Death: multi organ dysfunction syndrome (MODS)
25
Sepsis
26
Infection process: outcome
Symptomless
• subclinical, silent, inapparent (or very mild, non-specific symptoms)
• quick elimination of the pathogen
• very important: symptomless infections in childhood result in lifelong
immunity (e.g. toxoplasma) or cross immunity (HSV-1/HSV-2)
• Latent – the pathogen remains in the body, activates upon
intrinsic/extrinsic factors
• Persistent – Viral forms of latency – episomal (herpes) or integrated (retroviruses)
The pathogen activated regurarly, shed symptomless
(but infects others!)
• Carrier state – the pathogen is shed continuously w/o symptoms
(source of infection)
Manifest infection, manifestation of disease - symptoms are detected
• Acute (fulminant = extremely rapid course)
• Subacute
• Chronic
27
Infection process: outcome
Acute
Chronic
The pathogen disappears from the body →
reconvalescence → clinical recovery
Times of microbial and clinical recovery are different!
Acute (mainly fulminant)
Chronic
The pathogen remains in the body
No pathogen in the body, but
irreversible damages
death
The above courses are natural processes
Treatment (medication, antibiotics, vaccination, etc.) profoundly alters
disease course!
28
Defence mechanism against pathogenic
microbes
Unspecific factors
Inhibition of attachment, entry and facilitation of
removal
– skin integrity
– upward synchronised movement of cilia in the respiratory
tract
– pH – skin – organic acids, sebum
vagina – lactic acid (Lactobacilli) pH 4-5
stomach – HCl, pH 1-2
– enzymes – tear – lysozyme + blinking
mouth, gastrointestinal tract
– osmolarity – urine flow
– accelerated peristaltic movement, vomiting
29
The role if immune system in the
antimicrobial defense
Functions of the immune system
• recognition of pathogenic microbes (foreign, non-self)
• innate immunity – immediate onset of aspecific defense mechanisms
• depending on innate immunity: onset of adaptive immunity
• recognition of antigens, their presentation
• activation of signal transmission among different immune cell subsets
(interleukines, chemokines)
• mobilisation of the effector cells in the cellular and humoral immune
system
• destruction of microorganisms and infected cells
• elimination of debris produced from microbes, infected cells and
unnecessary immune cells
• establishment of immune memory
Primary infection = first encounter between the macro- and microorganism:
above reactions
Secondary/repeated infection by the same microbe: activation of immune
memory
30
Recognition of pathogenic microbes
Monocytes, macrophages, neutrophil phagocytes, dendritic cells
• Cell surface receptrors (C-type lectin, TLR1,2,4,5,6)
• Endosomal receptors (C-type lectin, TLR3,7,8,9)
Recognized molecules
• Conserved structures missing in mammalian organisms
pathogenic associated molecular pattern (PAMP)
LPS, Gram positive bacterial cell wall peptidoglycan, lipoteichoic
acid, flagellin, N-formylmethionin, hypomethylated CpG-DNA,
ss/dsDNA, ss/dsRNA
• Intracellular components of lysed infected (virus, bacteria,
protozoa) cells
damage associated molecular patterns (DAMP)
nuclear polypeptides, mitochondrial DNA, reactive oxygen radicals,
matrix proteins, heat shock proteins
31
Activation of the innate immunity
Augmented signal transduction from receptors →
cascade of events
• activation of interferon regulatory factors (IRF) → production
of interferons (IFN-α,-β,-γ,-λ) → activation of IFN-stimulated
genes (ISG, several hundreds) in immune and adjacent cells,
infected cells
• formation of intracellular inflammasomes (RIG-I, NLRP3, etc.)
and stress granules = protein complexes
• protein kinase R (PKR) activation → RNaseL activation
→degradation of foreign RNA
• caspase activation → programmed cell death of infected cells
• release of pro-inflammatory mediators (e.g. IL-1,-2,-8, TNF-α)
GM-CSF, G-CSF: phagocyte attraction
32
First signs of manifesting innate immunity
• Onset of inflammation
– localisation of infecting agents, preventing systemic
infection/damage
– increased circulation and permeability of capillary
membranes → oedema
– local and systemic effects of mediators
pro-inflammatory cytokines (IL-1,-8,-11, TNF-α, etc.)
anti-inflammatory cytokines (TGF-β, IL-4,-6,-10, etc.)
attraction of immune cells/phago-, monocytes,
macrophages, lymphocytes, etc.
– acute phase reaction (systemic effect: fever, malaise)
– production of C-reactive protein (CRP): opsonisation
and/or aggregation of bacteria
33
Contribution of the complement
system to innate immunity
Activation and effect through different routes
• Bacterial cell wall mannose → mannose binding lectin (MBL) →
MASP1/MASP2 protease activation → C4/C2 split → C3
convertase → production of C3a and C3b fragments
• C3a and C5a – neutrophil granulocyte chemotaxis
• C3b – opsonisation:
bacterium + C3b molecule + phagocyte complement receptor
enhanced phagocytosis
• C5b-C9 - binding Gram negative bacterial lipids → bacteriolysis
bacteriocidia
34
Opsonisation
35
The role of phagocytes in the innate immunity
Phagocytosis
• G-CFS, GM-CSF – augmented production, chemotaxis, tissue
entry
• main role: kill extracellular pathogens
Steps of action
• binding (opsonisation +/-) → engulfment and internalisation →
phagosome + lysosome fusion → killing in phagolysosome →
oxygen
dependent
(O2-, NO-)
oxygen independent
(enzymes: lysosyme,
lactoferrin, defensins)
→ digestion of killed microbes → cell death, debris → constituents
of pus
36
Natural killer cells
Role
• to attach and destroy infected cells
Natural killer (NK) cells
• large, granular lymphocytes
• TCR expression + Fc (CD16) receptor+, MHC-
Mechanism of killing
NK cell receptors + foreign antigen on target cells
FasL + Fas
Binding →
Production of perforin: pore formation in cell membrane of target cells
granzyme – intracellular induction of apoptosis
37
Adaptive immune response
Role
• selective destruction of pathogenic microbes
• antigen dependent
• different course in primary and secondary infections (immune memory)
Course
•
•
•
•
•
•
•
internalisation of antigens into antigen presenting cell (APC: MØ, DC)
proteolysis → peptide subunits carrying epitopes
presenting subunits on MHC-I or MHC-II molecules to effector cells
activation of effector cells
destruction of microorganism: by antibodies ← humoral immunity
destruction of infected cells:
cellular
cytotoxic cells ←
destruction of eukaryotic pathogen:
immunity
38
Adaptive immune response: activation of
effectors cells I
Cellular immunity
• cytotoxicity: naive CD8+TCR + APC MHC-I antigen peptide →
activation → binding infected cells → perforin/granzyme → cell
destruction
• helper function: naive CD4+TCR + APC MHC-II antigen peptide →
activation → cytokine production
– Th1 – boosting cellular immunity
– Th2 – boosting humoral immunity
Humoral immunity
• B cells: BCR + Ag (repetitive epitopes) → activation
BCR + Th2 cytokines + Ag → activation
Plasma cells → antibody = immune globulin (Ig) production +
immune memory
39
Adaptive immune response: activation of
effectors cells II
γ/δ T cells
• Phylogenetically early γ and δ TCR + Ag recognition w/o
MHC restriction → cytotoxic effects, cytokine
production
• γ/δ T cells + MHC-like CD1 + Ag → activation of Th1
cells → cytokine production – mucosal immunity
Treg (regulatory T cells)
• Control of immune reaction to inhibit immune
reactions against self Ag
• Abnormal functions in the elderly (immunosenescence)
40
Humoral immunity
Antibody classes
• IgM – produced in primary infection: rapid but transient effect
• IgG – later in the course of primary infections, lifelong existence
(seroconversion)
Rapid production at high level in secondary infections
• IgA – dimer, on the surfaces of the mucous membranes → mucosal immunity
MALT (BALT, GALT)
inhibition of binding of microbes to mucosal cell receptors
• IgD – “natural” antibody
• IgE – in allergic reactions
Functional groups
• Anti-adhesive antibodies, IgA – Gram+ bacteria: lipoteichoic acid
– Gram- bacteria: pili
• Neutralising antibodies – binding microbes (virions), exotoxins, enzymes
• Opsonising antibodies – Gram+ bacteria, capsule antigens → promoting
phagocytosis
41
Immune reactions against extracellular
bacteria I
Activation of the innate immunity
• Gram- bacterial LPS: macrophage activation → cytokine production
• Gram+ bacterial peptidoglycan: complement activation
(alternative route)
Complement activation → opsonisation
• Phagocyte Fc receptor + antibody Fc + complement → rapid,
efficient internalisation
Major role of antibodies
•
•
•
•
•
IgM/IgG binding → direct bacteriocidia
IgM – opsonisation, agglutination, lysis
IgG – neutralisation (bacteria, toxins)
Polysaccharide antigens → IgM (T independent B cell activation)
S. aureus TSST → CD4+ T cell activation → cytokine storm
42
Immune reactions against extracellular
bacteria II
Immune evasion by bacteria
• Defense strategies of microbes to avoid immune reactions
– Inhibition of innate immunity
weak TLR binding – S. typhi, Y. pestis, Francisella
– Capsule – New antigenic variations
Masking other antigens (O)
– S. aureus – Fibrin cover
Protein A: blocks Ig Fc fragment, host cell Ag mimicry
Catalase: inactivation of lysosomal enzymes
Leukocidin: membrane damage of phagocytes
– S. pyogenes – Streptolysin: damages lysosomal membranes
M protein: C3 inactivation
43
Immune reactions against intracellular
bacteria
Infection and survival in phagocytes and macrophages
•
•
•
•
Immune defense: mostly cellular immunity
CD4+ Th1 dominance → IL-12, TNF-α, IFN-γ production → MØ activation
MØ MHC-I – Ag-expression: CD8+ T cell and NK cell activation → cytotoxycity
APC MHC-II – Ag-expression → B cell activation → antibody production
Immune evasion by bacteria
• M. tuberculosis: macrophage damage, inhibition of activation by IFN-γ
• M. tuberculosis, Legionella, Chlamydia: inhibition of the fusion between
phagosome – lysosome
• Shigella, Listeria, Rickettsia: damages to lysosomal membrane
• Salmonella, Coxiella: inhibition of lysosomal enzymes
• Neisseria, enteric bacteria: Inhibition of complement activation
(“serum resistance”)
Inhibition of opsonisation
• Neisseria meningitidis B: self antigen mimicry
44
Immune defense against virus
infections
Viruses = intracellular parasites!
Definitive role of innate immunity
• NK cells activated by IL-12 destroy infected cells very early
The role of antibodies
• unenveloped viruses + Ab → phagocytosis
• enveloped viruses + Ab → lysis of virions
• neutralising antibodies
Destruction of infected cells
• phagocyte MHC-II Ag presentation → Activation of B cells
→ Activation of CD4+ T cells →
cytokine production
• many types of infected cells: MHC-I Ag presentation → CD8+ T cells activation
• cells + Ab + complement → lysis, phagocytosis
• ADCC: antibody dependent cellular cytotoxicity (NK Fc receptor + Ab binding)
45
Immune evasion by viruses
• Replication in immune cells (HIV, HHV-6, HHV-7 in
CD4+ cells)
• Persistence: episomal (Herpesviridae), integration
(Retroviridae)
• Cell-to-cell spread avoiding antibodies (Herpesviridae)
• Antigen variations - shift (influenzaviruses,
rhinoviruses)
• Inhibition of MHC synthesis (adenoviruses,
cytomegalovirus U18 gene product)
• Interleukin mimicry (Epstein-Barr virus vIL-10)
• Complement fragment neutralisation (HSV-1 – C3b)
46
Immune defense against protozoa
and helminths I
In common speech
– parasite = helminths, protozoa, arthropods (known for centuries)
– medical parasitology
– (microbes = bacteria, viruses, microscopic fungi)
Protozoa: single cell eukaryotes (microscopic size)
Helmiths: multicellular organisms (microscopic – extremely large size)
Immune defense
• inefficient, hardly known → chronic debilitating diseases
Innate immunity
• direct damage – phagocytosis
• alternative complement activation – lysis
Adaptive immuity
• cellular immunity against intracellular parasites
– cytotoxic T cells
– IFN-γ activated macrophages
47
Immune defense against protozoa
and helminths II
Adaptive immunity
• Humoral immunity against extracellular parasites
– Complement activation, antibodies: opsonisation, ADCC,
neutralisation
– Helminths: Local inflammation, granuloma = localisation → fibrosis
IgE and IgE-dependent cytotoxicity, allergy
Th2 cytokine dominance (IL-4, IFN-γ, TNF-α)
Immune evasion by parasites
• Replication inside cells (WBC, liver: malaria, MØ: toxoplasma)
• Protecting shell from host polypeptide (Schistosoma in the lung)
• Enzyme production (Leishmania: antibody digestion)
• Inhibition of phagolysosome fusion (Toxoplasma gondii)
• Solubilisation of phagolysosome membrane (Trypanosoma cruzi)
• Shift in antigen structure (vegetative forms/cysts)
• Generalized immune suppression
48
Immunisation
I
Aim: Immunisation, vaccination – to protect against invading pathogens
Different by historical times, geographical regions,
target populations
Forms: Active = to mimic primary infection – establishment of adaptive immunity
Passive = to substitute antibodies
Active immunisation
•
•
•
•
•
•
•
Introduction of antigen(s) in harmless form → primary infection → immune memory
Killed microbes
Living, attenuated (avirulent) microbes
Attenuated toxins (toxoid)
Components of microbes (antigen molecules: capsule polysaccahride, polypeptides)
– Artificially produced (HPV L1, HBV surface antigen)
– DNA vaccination (future)
Adjuvants
Slow effect (booster injections), lifelong effect
49
Active immunisation
50
Immunisation II
Passive immunisation
• Introduction of antibodies
• Natural: foetus, breast milk (IgG, IgA)
• Artificially: antibodies produced in animals,
human (poly-/monovalent), “γ-globulin”
• Immediate but transient effect, no immune
memory
Immunomodulation
• Immune therapy (oncology), anti-cytokine MAbs
51
Immunisation III
Risks and side effects of immunisation
• Reaction (normal) → complication (rare biological effects) → accident (by
the product or application)
• Active immunisation
– Living attenuated microbes: generalization (post-vaccination encephalitis)
– (mutants → reversion: e.g. poliomyelitis virus)
– Further mutations: loss of antigenicity (BCG)
• Passive immunisation
– Animal serum → hypersensitivity type I (anaphylaxia) and type III (Arthus
reaction, serum sickness)
Contraindications
• Acute infectious diseases (including incubation time)
• Immune system disorders, some forms of allergy
• Pregnancy (living attenuated microbes)
• Intervals between vaccination (weeks)
Controlling
• Public health authorities
52
Abnormal immune reactions:
hypersensitivity
Hypersensitivity reactions
Early types
• Type I Anaphylaxis
– Sensibilisation with Ag (microbes or products, pollen, metals, hay, chemicals, etc. →
IgE production → allergy, release of bioactive/vasoactive mediators + Th2 cytokines
→ shock (death)
– Generalized or local (skin)
• Type II Cytotoxic
– Cell surface Ag + IgM/IgG → complement mediated lysis, NK activity, ADCC
– Haptens, drugs, Rh incompatibility
• Type III Immune complex (Arthus) reaction, serum sickness
– Immune complexes are deposited in tissues → complement activation → chemotaxis
of PMNL → local tissue damage, inflammation
– (Kidney: glomerulonephritis)
Late type
• Type IV Cell mediated hypersensitivity
– Intrcellular Ag → Th1 cytokine production → local inflammation → macrophage/T
cell concentration → granuloma
53
– Tuberculin allergy, Mantoux test
54
Hypersensitivity reactions
Autoimmunity and immune tolerance
Immune tolerance
• No immune response to a particular antigen/antigens
• Most important: self antigens
• Clonal selection, clonal allergy – established in foetus
Automimmunity
• Immune reactions to self (own) antigens
• Released of sequestered antigens (cell damage)
mumps virus → damage of testicular cells → inflammation → infertility
• Cross reacting antibodies (microbial antigen ≡ self antigen)
Streptococcus M protein – heart muscle
adenoviruses – α-gliadin
Klebsiella – HLA-B27
Treponema pallidum – cardiolipin
Campylobacter jejuni – gangliosides
Blocking antibodies, idiotype network
• Variable (V) region of antibodies ≈ foreign (?) → anti-idiotypic antibodies →
binding → blocking → termination of antibody response
55